WO2020240483A1 - Combinaison d'un acide biliaire polyhydroxylé et d'un agoniste du récepteur farnésoïde x - Google Patents

Combinaison d'un acide biliaire polyhydroxylé et d'un agoniste du récepteur farnésoïde x Download PDF

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WO2020240483A1
WO2020240483A1 PCT/IB2020/055097 IB2020055097W WO2020240483A1 WO 2020240483 A1 WO2020240483 A1 WO 2020240483A1 IB 2020055097 W IB2020055097 W IB 2020055097W WO 2020240483 A1 WO2020240483 A1 WO 2020240483A1
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Prior art keywords
bile acid
acid
bile
farnesoid
polyhydroxylated
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PCT/IB2020/055097
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English (en)
Inventor
Victor Ling
Lin Liu
Jonathan Ahab Sheps
Renxue Wang
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Qing Bile Therapeutics Inc.
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Priority to CN202080039658.7A priority Critical patent/CN113950329A/zh
Priority to US17/614,679 priority patent/US20220227804A1/en
Publication of WO2020240483A1 publication Critical patent/WO2020240483A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton

Definitions

  • the present invention provides a combination therapy. More specifically, the present invention provides a combination therapy including a polyhydroxylated bile acid and a farnesoid X receptor agonist.
  • BACKGROUND OF THE INVENTION [0002] Bile is a complex secretion produced by the liver. It is stored in the gall bladder and periodically released into the small intestine to aid in digestion. Bile components include cholesterol, phospholipids, bile pigments, and various toxins that the liver eliminates through biliary/fecal exclusion. Bile salts are synthesized and actively secreted across canalicular membranes providing the osmotic force to drive the flow of bile.
  • Bile flow is essential for liver detoxification, digestion, cholesterol metabolism, and absorption of lipid-soluble nutrients and vitamins.
  • Bile acids are critical as carriers for elimination of cholesterol from the body through biliary secretion and as a detergent for the ingestion of fatty acids and fat-soluble vitamins (1). Bile acids also play important roles in regulating cell apoptosis/survival (2; 3; 4; 5; 6) and in regulating gene expression through the farnesoid X receptor (FXR) (7; 8; 9; 10; 11; 12) in hepatocytes.
  • FXR farnesoid X receptor
  • Bile acids are synthesized in hepatocytes from cholesterol, secreted into the bile after being conjugated at the C24 position with glycine or taurine, reabsorbed in the small intestine, and recirculated back to hepatocytes through the portal vein. Canalicular secretion of bile acids from liver into the bile is a key process in the enterohepatic circulation of bile acids and its malfunction results in different hepatic diseases (1). If this process is disrupted, accumulation of bile acids often causes liver damage due to detergent effects. In humans, the bile acid pool circulates 6-10 times every 24 h, resulting in daily bile salt secretion of 20-40 g in about 400 ml (13; 14). [0004] Common bile acids found in the bile of selected mammals include the following:
  • THBAs Tetrahydroxylated bile acids
  • the farnesoid X receptor also known as the bile acid receptor (BAR) or NR1H4 (nuclear receptor subfamily 1, group H, member 4) is a member of the nuclear receptor (NR) superfamily that is encoded by the NR1H4 gene in humans.
  • FXR has been implicated in the regulation of bile acid synthesis, conjugation and transport (36)
  • Obeticholic acid (OCA) the 6a-ethyl derivative of chenodeoxycholic acid (CDCA)
  • OCA efficiently inhibits bile acid synthesis, reducing circulating bile acids through FXR mediated gene regulation.
  • OCA as the drug product OCALIVA ® is approved by the FDA for the treatment of primary biliary cholangitis (PBC) in adult patients. OCA has also been indicated for the treatment of PBC in combination with UDCA in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA. High- dose OCA in combination with UDCA has been reported to cause jaundice in those patients who do not benefit from UDCA monotherapy (15).
  • Tropifexor (TXR), 2-[(1R,5S)-3-[[5-Cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2- oxazol-4-yl]methoxy]-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid, is an agonist of FXR that is under investigation for the treatment of cholestatic liver disease and nonalcoholic steatohepatitis.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising i) a polyhydroxylated bile acid; and ii) an inoperable amount of a farnesoid X receptor agonist, in combination with a pharmaceutically acceptable carrier.
  • the inoperable amount of a farnesoid X receptor agonist may be a subtherapeutic amount or a toxic amount.
  • the ratio of the farnesoid X receptor agonist to the polyhydroxylated bile acid may be equal to or less than 1:100.
  • the farnesoid X receptor agonist may be obeticholic acid or tropifexor;
  • the polyhydroxylated bile acid may be a tetrahydroxylated bile acid, such as 3 a, 6 a, 7 a, 12 a- tetrahydroxy-5 b-cholan-24-oic acid; and/or the tetrahydroxylated bile acid may be a conjugated compound, such as a taurine or a glycine conjugate.
  • the present invention provides a method of treating a biliary disorder or a gastrointestinal disorder by administering a composition as described herein to a subject in need thereof.
  • the biliary disorder may arise from cholestasis; the gastrointestinal disorder may be an inflammatory disorder.
  • the present invention provides a method for reducing the toxicity of a farnesoid X receptor agonist by comprising i) a polyhydroxylated bile acid; and ii) a toxic amount of a farnesoid X receptor agonist, in combination with a pharmaceutically acceptable carrier.
  • the present invention provides a method for enhancing the therapeutic effect of a farnesoid X receptor agonist by comprising i) a polyhydroxylated bile acid; and ii) an inoperable amount of a farnesoid X receptor agonist, in combination with a pharmaceutically acceptable carrier.
  • the farnesoid X receptor agonist may be obeticholic acid or tropifexor;
  • the polyhydroxylated bile acid may be a tetrahydroxylated bile acid such as 3 a, 6 a, 7 a, 12 a-tetrahydroxy-5 b-cholan-24-oic acid; and/or the tetrahydroxylated bile acid may be a conjugated compound, such as a taurine or a glycine conjugate and/or the subject may be a human.
  • the present invention provides the use of a composition as described herein in the preparation of a medicament.
  • the composition may be used in treating a biliary disorder or a gastrointestinal disorder.
  • the present invention provides an article of manufacture or a kit including a composition as described herein, together with instructions treating a biliary disorder or a gastrointestinal disorder.
  • FIGURE 1 shows bilirubin, ALT, ALP and total bile acids in the plasma of Mdr2 -/- mice under monotreatment conditions fed either 1% THBA (w/w), 0.03% OCA (w/w), or control diet for 17 weeks from 3 weeks of age to 20 weeks.
  • FIGURE 2 shows bilirubin, ALT, ALP and total bile acids in the plasma of Mdr2 -/- mice under treatments of different dose combinations of 1% THBA (w/w) with or without different doses of OCA (0.03%, 0.01% and 0.003% (w/w)), or control diet, for 4 weeks from 8 weeks to 12 weeks of age.
  • FIGURE 3 shows ALP in the plasma of Mdr2 -/- mice under treatments of different dose combinations of TXR (0.00001% and 0.000003% (w/w)), 1% THBA (w/w) with or without different doses of TXR (0.00001% and 0.000003% (w/w)), or control diet.
  • Asterisks indicate statistical significance by one-way ANOVA (Tukey's multiple comparison) of each pair of TXR treatments against either THBA-fed or control diet groups.
  • the present disclosure provides, in part, a combination therapy including a
  • the present disclosure provides a combination therapy including a tetrahydroxylated bile acid (THBA) and a farnesoid X-activated receptor (FXR) agonist.
  • THBA tetrahydroxylated bile acid
  • FXR farnesoid X-activated receptor
  • the polyhydroxylated bile acids can be agents of bile salt therapy to promote or improve biliary secretion, in combination with an FXR agonist, in subjects with biliary disorders or gastrointestinal (GI) disorders.
  • a combination therapy according to the present disclosure can further be used in combination with additional known compounds, such as ursodeoxycholate or a variant or derivative thereof, to improve liver function and/or ameliorate a bile or GI disorder.
  • the claimed composition can result in reduced liver injury, for example in cholestatic diseases, or reduced intestinal injury, for example in inflammatory GI disorders.
  • the claimed composition can reduce the toxicity and/or hydrophobicity of the bile acid pool.
  • the claimed composition can reduce the production of toxic bile acids, such as chenodeoxycholic acid (CDCA).
  • the claimed composition can stimulate bile flow.
  • the claimed composition can reduce the toxicity of an FXR agonist.
  • the present disclosure provides a method for reducing the toxicity of a farnesoid X receptor agonist by administering a polyhydroxylated bile acid in combination with a toxic amount of a farnesoid X receptor agonist to a subject in need thereof, where the amount of the polyhydroxylated bile acid is sufficient to substantially counteract the toxicity of the farnesoid X receptor agonist. It is to be understood that some level of toxicity may be acceptable, as described herein.
  • the reduction in toxicity can be compared, for example, in comparison to the toxicity of the farnesoid X receptor agonist when administered as a monotherapy. Toxicity can be measured using standard techniques as described herein or known in the art. [0028] In some embodiments, the claimed composition can reduce the production of
  • hydrophobic primary bile acids cholic acid (CA) and CDCA reduces the production of hydrophobic secondary bile acids lithocholic acid (LCA) and deoxycholic acid (DCA).
  • the polyhydroxylated bile acids can be choleretic (possess bile flow-stimulating properties) when administered to a subject.
  • the polyhydroxylated bile acids can stimulate bile flow in any subject, for example, a subject not diagnosed with a GI or biliary disorder.
  • a subject may be a human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc.
  • the subject may be a clinical patient, a clinical trial volunteer, an experimental animal, etc.
  • the subject may be suspected of having or be at risk for having a GI or biliary disorder, be diagnosed with a GI or biliary disorder, or be a subject confirmed to not have a GI or biliary disorder. Diagnostic methods for GI or biliary disorders and methods for measurement of bile flow, as well as the clinical delineation of GI or biliary disorder diagnoses, are known to those of ordinary skill in the art.
  • Biliary disorders include any disorder or condition that can be ameliorated, treated or prevented by the administration of a polyhydroxylated bile acid.
  • Exemplary biliary disorders may include without limitation bile deficiency, bile toxicity, digestive disorders, impaired liver function, cholestasis, portal hypertension, etc.
  • biliary disorders include any condition that is known to be, or is expected to be, responsive to a therapy that: improves bile flow, improves biliary secretion, reduces the production of hydrophobic primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA), reduces the production of toxic bile acids (such as lithocholic acid (LCA) and deoxycholic acid (DCA)) and/or reduces the hydrophobicity of the bile acid pool.
  • CA hydrophobic primary bile acids
  • DAA deoxycholic acid
  • Cholestasis refers to a condition in which the flow of bile from the liver is reduced or blocked, or in which there is a failure in bile flow. Bile flow failures may arise anywhere in the hepatic and biliary system. In general, cholestasis may be extrahepatic cholestasis, which occurs outside the liver cells, or may be intrahepatic cholestasis, which occurs inside the liver cells.
  • Extrahepatic cholestasis can result from benign biliary strictures, benign pancreatic disease cysts, diverticulitis, liver damage, common bile duct stones, pancreatitis, pancreatic cancer or pseudocyst, periampullary cancer, bile duct carcinoma, primary sclerosing cholangitis, or extrinsic duct compression, for example, compression due to a mass or tumor on a nearby organ.
  • Intrahepatic cholestasis can be caused by viral hepatitis including but not limited to Hepatitis B and C, sepsis, bacterial abscess, drugs e.g., drug-induced idiosyncratic
  • hepatotoxicity lymphoma, tuberculosis, metastatic carcinoma, sarcoidosis, amyloidosis, intravenous feeding, primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis with or without cirrhosis, chronic hepatitis with or without cirrhosis, pregnancy, Sjogren syndrome, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic hepatitis with or without cirrhosis, intrahepatic cholestasis of pregnancy, PFIC, etc.
  • Drug-induced cholestasis is the blockage of the flow of bile from the liver caused by medication, and may be caused by: gold salts, nitrofurantoin, anabolic steroids, oral contraceptives, chlorpromazine, prochlorperazine, sulindac, cimetidine, erythromycin, tobutamide, imipramine, ampicillin and other penicillin- based antibiotics, etc.
  • Drug-induced cholestasis and hepatotoxicity are common obstacles to drug therapy in the clinic and pose major problems for drug development and for novel applications of approved drugs. Drug-induced cholestasis also accounts for 2-5% of patients hospitalized with jaundice, ⁇ 10% of all cases of acute hepatitis, and over 50% of acute liver failure.
  • Cholestasis may also result from inherited cholestatic liver disease, from drug-induced cholestasis arising from certain drugs, and acute hepatotoxic reactions brought about by drugs and inflammatory conditions which impact liver function.
  • Portal hypertension refers to a disorder manifesting as increased pressure in the portal vein, which is the vein that conducts blood from the intestine to the liver.
  • the increased pressure in the portal vein may be due to a variety of causes, including inflammation, fibrosis, splenic arteriovenous fistulae, splenic or portal vein thrombosis, massive splenomegaly, sarcoidosis, schistosomiasis, nodular regenerative hyperplasia, primary biliary cirrhosis, hepatitis, autoimmune disease, etc.
  • a biliary disorder according to the invention is any disorder arising, or potentially arising, from cholestasis, portal hypertension, or any disorder benefited by the administration of a combination therapy as described herein.
  • Biliary disorders include without limitation benign biliary strictures, benign pancreatic disease cysts, diverticulitis, liver fibrosis, liver damage, common bile duct stones, pancreatitis, pancreatic cancer or pseudocyst, periampullary cancer, bile duct carcinoma, primary sclerosing cholangitis, autoimmune cholangitis, extrinsic duct compression (e.g., compression due to a mass or tumor on a nearby organ, viral hepatitis (e.g., Hepatitis A, B, C, D, E, herpes simplex, cytomegalovirus, Epstein-Barr, adenovirus), sepsis, bacterial abscess, use of drugs e.g., drug-induced idiosyncratic hepatotoxicity, lymphoma, tuberculosis, metastatic carcinoma, sarcoidosis, amyloidosis, intravenous feeding, primary biliary
  • Gastrointestinal disorders include any disorder or condition that have as contributory factor inflammation of the gastrointestinal tract caused, or exacerbated, by bile acids.
  • a GI disorder is an inflammatory GI disorder, such as inflammation in the intestinal region of a subject.
  • an inflammatory GI disorder may include, without limitation, necrotizing enterocolitis (NEC), gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, pseudomembranous colitis,
  • Bile Acids are amphipathic compounds derived from cholesterol and are a subclass of steroids. Bile acids and bile alcohols are steroids whose structure is related to cholane or cholestane; accordingly, bile acids and bile alcohols may be termed cholanoids (13).
  • bile acid is a generic term for cholanoid molecules having a carboxyl group and does not denote an ionization state.
  • the term“bile salt” may be used for a salt in which the anion is a conjugated bile acid, an unconjugated bile acid, or a conjugate of a bile alcohol, or may be used as a generic term to include both conjugated bile acids and bile alcohol conjugates occurring in nature as water- soluble anions (13).
  • bile salts may be bile acids conjugated with glycine or taurine as sodium salts.
  • the bile acids may have various hydroxyl groups, such as dihydroxylated bile acids, trihydroxylated bile acids, tetrahydroxylated bile acids, and pentahydroxylated bile acids, e.g., cholic acid, ursodeoxycholic acid, nor-ursodeoxycholic acid, chenodeoxycholic acid, deoxycholic acid, muricholic acid.
  • cholic acid ursodeoxycholic acid
  • nor-ursodeoxycholic acid chenodeoxycholic acid
  • deoxycholic acid muricholic acid.
  • C24 bile acids are termed cholanoic acids or cholanoates, while C27 bile acids are termed cholestanic acids or cholestanoates.
  • the configuration of the side chain is 17 b, with a 5 b hydrogen (A/B ring junction in cis configuration).“Allo” bile acids are bile acids with a 5 a hydrogen (13).
  • Bile acids may be polyhydroxylated. Polyhydoxylated bile acids, in accordance with the present disclosure, are those with four or more hydroxyl groups. Accordingly, a
  • polyhydroxylated bile acid compound according to the invention includes without limitation tetrahydroxylated bile acids, pentahydroxylated bile acids, hexahydroxylated bile acids, etc., up to the maximum level of hydroxylation possible.
  • a tetrahydroxylated bile acid may be a compound as represented in Formula I:
  • any four of R1 to R9 may be––OH and R10 may be–COOH or–CH2OH.
  • any four of R1 to R9 may each independently be -OH, -F, -Cl, -Br, alkyl (for example, -CH3, -CH2-CH3), -SO4, or glucose and R10 may be–COOH or–CH2OH.
  • polyhydroxylated bile acids according to the invention are at least tetrahydroxylated i.e. have four or greater than four hydroxyl groups. In some embodiments, the hydroxyl groups are present on the steroid nucleus.
  • a tetrahydroxylated bile acid according to the invention includes, without limitation, a 3,6,7,12-tetrahydroxycholanoic acid; a 3,4,7,12-tetrahydroxycholanoic acid; a 1,2,7,12- tetrahydroxycholanoic acid; a 1,3,7,12-tetrahydroxycholanoic acid; a 2,3,7,12- tetrahydroxycholanoic acid; a 3,7,16,24-tetrahydroxycholanoic acid; or a 3,7,15,24- tetrahydroxycholanoic acid, or derivatives thereof.
  • a 3,6,7,12-tetrahydroxycholanoic acid includes, without limitation, a 3 a, 6 a, 7 a, 12 a-tetrahydroxy-5 b-cholan-24-oic acid; a 3 a, 6 b, 7 a, 12 a- tetrahydroxy-5 b-cholan-24-oic acid; a 3 a, 6 a, 7 b, 12 a-tetrahydroxy-5 b-cholan-24-oic acid; a 3 a, 6 b, 7 b, 12 a-tetrahydroxy-5 b-cholan-24-oic acid; a 3 a, 6 a, 7 a, 12 b-tetrahydroxy-5 b-cholan- 24-oic acid; a 3 a, 6 b, 7 a, 12 b-tetrahydroxy-5 b-cholan-24- 24-oic acid; a 3 a, 6 b, 7 a, 12 b-tetrahydroxy-5 b-chol
  • a 3,4,7,12-tetrahydroxycholanoic acid according to the invention includes, without limitation, a 3a ,4b ,7a ,12a tetrahydroxy-5 b-cholan-24-oic acid, a 3a, 4 a, 7 a, 12 a- tetrahydroxy-5 b-cholanoic acid, or derivatives thereof.
  • a 1,3,7,12-tetrahydroxycholanoic acid according to the invention includes, without limitation, a 1b , 3a , 7a , 12a ,etrahydroxy-5 b-cholan-24-oic acid, or derivatives thereof.
  • a 2,3,7,12-tetrahydroxycholanoic acid according to the invention includes, without limitation, a 2b , 3a , 7a , 12a tetrahydroxy-5b-cholan-24-oic acid, a 2 a, 3 a, 7 a, 12 a- tetrahydroxy-5 b-cholanoic acid, or derivatives thereof.
  • a 3,7,16,24-tetrahydroxycholanoic acid according to the invention includes, without limitation, a 3a , 7a , 16a , 24 tetrahydroxy-5 b-cholane or derivatives thereof.
  • a 3,7,15,24-tetrahydroxycholanoic acid includes without limitation, a 3a , 7b , 16a , 24 tetrahydroxy-5 b-cholane or derivatives thereof.
  • polyhydroxylated bile acid compounds according to the invention include, without limitation, a 3a , 7a , 12a , 24 tetrahydroxy- 5b-26-oic acid; a
  • polyhydroxylated bile acid compounds according to the invention are more hydrophilic than cholate (1, 16), as measured for example by the distribution and configurations of polar [OH-] and apolar (H + ) residues along the steroid ring, or by retention times in reverse-phase HPLC (17).
  • polyhydroxylated bile acid compounds according to the invention have a hydrophobicity of less than 0.45, 0.40, 0.35, 0.30, 0.25, 0.20, 0.15, 0.10, or 0.05 relative to taurocholate (which is assigned a value of 1.0; see for example Asamoto et al. (18)).
  • the term“conjugated bile acid” may be used to indicate a bile acid conjugated to a group that gives additional hydrophilicity or charge to the molecule.
  • the polyhydroxylated (such as tetrahydroxylated) bile acid compounds according to the invention include taurine and/or glycine conjugates.
  • the polyhydroxylated (such as tetrahydroxylated) bile acid compounds according to the invention include conjugates with any other suitable amino acids.
  • the polyhydroxylated (such as tetrahydroxylated) bile acid compounds according to the invention include conjugates with sulfate, phosphate, Coenzyme A, glucuronate, glucose, xylose, and other sugars, N- acetylglucosamine, etc.
  • conjugated polyhydroxylated (such as tetrahydroxylated) compounds according to the invention include, without limitation, tauryl or glycyl conjugates of 3 a, 6 b, 7 a, 12 b-tetrahydroxy-5 b-cholan-24-oic acids, tauryl or glycyl conjugates of 3 a, 6 b, 7 b, 12 b-tetrahydroxy-5 b-cholan-24-oic acids, tauryl conjugates of 3 a, 6 b, 7 a, 12 a-tetrahydroxy-5 b- cholan-24-oic acids, tauryl conjugates of 3 a, 6 b, 7 b, 12 a-tetrahydroxy-5 b-cholan-24-oic acids, ethanesulfonic acid, 2-[(3,6,7,12-tetrahydroxy-24-oxocholan-24- yl)amino], e.g., ethanesulfonic acid, 2-[[(3 ethan
  • the polyhydroxylated (such as tetrahydroxylated) bile acid compounds are conjugated with a group as described herein or known in the art at position 24 of the alkyl side chain.
  • a polyhydroxylated (such as tetrahydroxylated) bile acid compound may be conjugated with taurine or glycine at position 24 of the alkyl side chain of the polyhydroxylated (such as tetrahydroxylated) bile acid.
  • the polyhydroxylated (such as tetrahydroxylated) bile acid compounds according to the invention include isomers e.g., stereoisomers. For example, 3 b and 5 a hydroxy
  • tetrahydroxycholanoic acid are included, as are any stereoisomeric configurations and combinations thereof.
  • the polyhydroxylated (such as tetrahydroxylated) bile acid compounds according to the invention include physiologically or pharmaceutically-acceptable derivatives, such as salts, esters, enol ethers, enol esters, solvates, hydrates and prodrugs of the compounds described herein.
  • Pharmaceutically-acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole,
  • amine salts such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole,
  • alkali metal salts such as but not limited to lithium, potassium and sodium
  • alkali earth metal salts such as but not limited to barium, calcium and magnesium
  • transition metal salts such as but not limited to zinc, aluminum, and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate
  • salts of mineral acids such as but not limited to hydrochlorides and sulfates
  • salts of organic acids such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates and fumarates.
  • substantially pure or“isolated” when it is separated from the components that naturally accompany it (e. g, cells of a source organism or tissue).
  • a compound may be substantially pure or isolated when it is substantially free of cellular contaminants, i.e, that it is present ex vivo and in a concentration greater than that of the compound in a source organism, tissue, or other natural source.
  • a compound is substantially pure or isolated when it is at least 10%, 20%, 30%, 40%, 50%, or 60%, more generally 70%, 75%, 80%, or 85%, or over 90%, 95%, or 99% by weight, of the total material in a sample.
  • a compound that is chemically synthesized will generally be substantially free from its naturally associated components.
  • a substantially pure compound can be obtained, for example, by extraction from a natural source or by chemical synthesis.
  • a substantially pure compound may include stereoisomers or
  • a composition comprising a racemic mixture of a polyhydroxylated (such as tetrahydroxylated) bile acid is provided.
  • the racemic mixture may be produced as a result of the chemical synthesis of the polyhydroxylated (such as tetrahydroxylated) bile acid; alternatively, two or more stereochemically pure enantiomers may be combined.
  • the composition may comprise two or more
  • Farnesoid-X Receptor Agonists Farnesoid X receptor (FXR) is a nuclear receptor expressed at high levels in the liver, intestine, kidney, adrenal glands, and adipose tissue.
  • FXR agonists include without limitation, obeticholic acid (OCA), the 6a-ethyl derivative of chenodeoxycholic acid (CDCA), cafestol, fexaramine, Cilofexor (2-[3-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4- isoxazolyl]methoxy]phenyl]-3-hydroxy-1-azetidinyl]-4-pyridinecarboxylic acid), MET409 (Metacrine, Inc.), EDP-305 (Enanta Pharmaceuticals, Inc.), Tropifexor (2-[(1R,5S)-3-[[5- Cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methoxy]-8- azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-car
  • THBA compounds according to the invention or for use according to the invention, including pharmaceutically acceptable salts or derivatives thereof, may be obtained by synthesis making use of common procedures as exemplified herein or known in the art. Such synthetic THBA compounds can, optionally, be labeled or derivatized for analytical or drug development purposes.
  • THBA compounds may be synthesized using standard techniques such as those described in Tohma et al., 1985 (19); Iida et al, 1991a (20); Iida et al., 1991b (21); Aggarwal et al., 1992 (22); Iida et al., 1993 (23); Kurosawa et al, 1995 (24); Kurosawa et al., 1996 (25); Iida et al, 2002 (26); Tserng KY and Klein PD (1977) (27), Leppik RA (1983) (28), or Iida T. et al. (1990) (29, 30) etc., all of which are specifically incorporated by reference.
  • THBAs may be prepared as indicated in Tohma et al., 1985 (19); Iida et al., 1991b (21);
  • THBA compounds may be synthesized as, for example, described in WO
  • FXR agonists according to the invention, or for use according to the invention, including pharmaceutically acceptable salts or derivatives thereof, may be obtained by synthesis making use of common procedures as exemplified herein or known in the art. Such synthetic FXR agonists compounds can, optionally, be labeled or derivatized for analytical or drug development purposes.
  • FXR agonists may be obtained from commercial sources or prepared as described, for example, in 31; 32) [0070] Pharmaceutical Compositions, Dosages, and Administration [0071] Polyhydroxylated bile acids, such as tetrahydroxylated bile acids, can be provided in combination with FXR agonists (the“claimed combination” or the“combination therapy” in accordance with the present disclosure). [0072] In some embodiments, the amount of the FXR agonist can be an inoperable dose, for example a subtherapeutic dose, a subclinical dose, or a toxic dose.
  • an inoperable dose may vary depending on the subject or patient (e.g., adult, pediatric, geriatric or a subject or patient have a comorbidity that can affect dosage regimens).
  • the FXR agonist is provided at a lower dose than the bile acid.
  • the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be equal to or less than about 1:100 (w/w).
  • the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be equal to or less than about 1:300 (w/w). In some embodiments, the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be equal to or less than about 1:500 (w/w).
  • the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be equal to or less than about 1:1000 (w/w). In some embodiments, the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be equal to or less than about 1:100000 (w/w).
  • the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be about 1:100 to about 1:300 (w/w), or any value in between. In some embodiments, the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be about 1:50 to about 1:500 (w/w), or any value in between.
  • the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be greater than 1:30. In some embodiments, the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be greater than 1:30 to equal to or less than about 1:100000 (w/w), or any value in between.
  • the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be equal to or less than 1:100 (w/w). In some embodiments, the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be equal to or less than 1:300 (w/w).
  • the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be equal to or less than 1:500 (w/w). In some embodiments, the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be equal to or less than 1:1000 (w/w).
  • the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be equal to or less than 1:100000 (w/w). In some embodiments, the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be 1:100 to 1:300 (w/w), or any value in between.
  • the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be 1:50 to 1:500 (w/w), or any value in between. In some embodiments, the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be greater than 1:30.
  • the ratio of the FXR agonist, such as OCA or tropifexor, to the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, in the claimed combination can be greater than 1:30 to equal to or less than 1:100000 (w/w), or any value in between. [0076] In some embodiments, the ratio of the FXR agonist to the bile acid in the claimed combination can be less than the levels required for co-crystallization. [0077] In some embodiments, the polyhydroxylated bile acid, such as a tetrahydroxylated bile acid, can be administered in a range from about 50 mg per adult subject per day to about 5000 mg per adult subject per day.
  • the FXR agonist for example OCA or tropifexor, can be administered at less than about 1 mg per adult subject per day.
  • the FXR agonist can be administered at a dose at or below the minimal therapeutically effective dose or dose which exhibits no therapeutic benefit in the treatment of a GI or biliary disorder (a“subtherapeutic” dose).
  • the FXR agonist can be administered at a dose below the minimal dose used in standard clinical practice in the treatment of a GI or biliary disorder (a“subclinical” dose).
  • OCA may be administered at a dose less than about 5 - about 10 mg per day or any value in between (about 74 ug/kg daily for a person of about 70 kg body weight);
  • EDP-305 may be administered at a dose less than about 1 mg per day (about 14 ug/kg daily for a person of about 70 kg body weight);
  • Cilofexor may be administered at a dose less than about 30 mg per day (about 0.45 mg/kg daily for a person of about 70 kg body weight); tropifexor may be administered at a dose less than about 0.01 mg per day (about 0.15 ug/kg daily for a person of about 70 kg body weight); or
  • LMB763 may be administered at a dose less than about 5 mg per day (about 74 ug/kg daily for a person of about 70 kg body weight).
  • the FXR agonist can be administered at less than or equal to one- fifth of the standard recommended dosage for that compound.
  • OCA may be administered at less than or equal to one-fifth of about 5 - about 10 mg per day or any value in between (about 74- about 148 ug/kg daily for a person of about 70 kg body weight);
  • EDP-305 may be administered at less than or equal to one-fifth of about 1 - about 2.5 mg per day or any value in between (about 14 - about 36 ug/kg daily for a person of about 70 kg body weight);
  • Cilofexor may be administered at less than or equal to one-fifth of about 30 - about 100 mg per day or any value in between (about 0.45 - about 1.5 mg/kg or any value in between daily for a person of about 70 kg body weight); tropifexor may be administered at less than or equal to one- fifth of about 0.01 - about 0.03 mg per day or any value in between (about 0.15- about 0.45
  • the claimed composition may include 3 a, 6 a, 7 a, 12 a- tetrahydroxy-5 b-cholan-24-oic acid at a dosage of about 15 mg/Kg/day in combination with OCA at a dosage of about 0.05 mg/Kg/day (33; 34).
  • the claimed composition may include 3 a, 6 a, 7 a, 12 a- tetrahydroxy-5 b-cholan-24-oic acid at a dosage of about 15 mg/Kg/day in combination with tropifexor at a dosage of about 0.0004 mg/Kg/day.
  • the amount of FXR agonist, such as OCA or tropifexor, in the claimed composition may be substantially less than the amount used in current therapeutic practice.
  • adult human patients are dosed with OCA at about 5 mg per week to about 10 mg per day, or any value in between, depending on how well the dose is tolerated, whether the patient has decompensated liver disease and/or whether the patient is also taking UDCA.
  • adult human patients are dosed with tropifexor at about 3 mg per week to about 0.03 mg per day, or any value in between, depending on how well the dose is tolerated.
  • the FXR agonist such as OCA or tropifexor, may be used at a dosage“less than an effective dose.”
  • a dosage“less than an effective dose” is meant a dose that is less than the dose used in current therapies or which exhibits no therapeutic benefit e.g., a
  • subtherapeutic dose a subclinical dose.
  • “less than an effective dose” is meant a dose that is less effective or ineffective when used as a monotherapy, or in combination with UDCA, or in combination with a compound other than a bile acid, when treating a biliary or GI disorder.
  • a dose that is less effective is a dose that is 5% to 99% percent, or any value in between, such as 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, less effective when used as a monotherapy, or in combination with UDCA, or in combination with a compound other than a bile acid, when treating a biliary or GI disorder, compared to the same dose when combined with a polyhydroxylated bile acid, such as a THBA.
  • the FXR agonist such as OCA or tropifexor
  • toxic dose is meant a dose or amount that results in an unacceptable toxicity level, when used as a monotherapy, or in combination with UDCA, or in combination with a compound other than a bile acid, when treating a biliary or GI disorder, compared to the same dose or amount when combined with a polyhydroxylated bile acid, such as a THBA, as described herein.
  • a toxic dose or amount is that which increases the level of one or more liver indicators, such as bilirubins, ALP (alkaline phosphatase), ALT (alanine aminotransferase), AST (aspartate aminotransferase), g-GT (Gamma-Glutamyl Transpeptidase), etc. to outside the normal clinical range in a subject or which further increases the level of one or more liver indicators, such as bilirubins, ALP (alkaline phosphatase), ALT (alanine
  • liver indicators such as bilirubins, ALP (alkaline phosphatase), ALT (alanine aminotransferase), AST (aspartate aminotransferase), g-GT (Gamma-Glutamyl Transpeptidase), etc. in a subject having higher levels of the one or more liver indicators.
  • the level of increase of liver indicators such as bilirubins, ALP (alkaline phosphatase), ALT (alanine aminotransferase), AST (aspartate aminotransferase), g-GT (Gamma-Glutamyl
  • Transpeptidase can be about 5% to about 100% percent, or any value in between, such as 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% increase. In some
  • the level of increase of liver indicators such as bilirubins, ALP (alkaline phosphatase), ALT (alanine aminotransferase), AST (aspartate aminotransferase), g-GT
  • liver-Glutamyl Transpeptidase can be over 100% percent, compared to normal clinical values or ranges.
  • Normal clinical values and ranges for liver indicators are well known.
  • the normal clinical ranges for selected liver indicators may be as follows:
  • Bilirubin 2 to 17 micromoles/L; ALP (alkaline phosphatase): 30 to 120 IU/L; ALT (alanine aminotransferase): 0 to 45 IU/L; AST (aspartate aminotransferase): 0 to 35 IU/L; g-GT (Gamma- Glutamyl Transpeptidase): 0 to 30 IU/L.
  • An“effective amount” of a combination according to the invention includes a
  • A“therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as increased bile flow, relief of jaundice, or improved liver functions as indicated by normalization of serum liver biochemical indicators, such as the levels of bilirubins, ALP (alkaline phosphatase), ALT (alanine aminotransferase), AST (aspartate aminotransferase), g-GT (Gamma-Glutamyl
  • a therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects.
  • A“prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as increased bile flow or improved liver functions as indicated by liver biochemical indicators, increased bile flow, relief of jaundice, or improved liver functions as indicated by normalization of serum liver biochemical indicators, such as the levels of bilirubins, ALP (alkaline
  • a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount may be less than a therapeutically effective amount.
  • An exemplary range for therapeutically or prophylactically effective amounts of a compound may be about 5- about 50 mg/day/kg of body weight of the subject e.g., a human.
  • A“nutritionally effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired result, such as increased bile flow or improved liver functions as indicated by liver biochemical indicators. [0088] It is to be noted that dosage values may vary with the severity of the condition to be alleviated.
  • dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • Dosage ranges set forth herein are exemplary only and do not limit the dosage ranges that may be selected by medical practitioners.
  • the amount of active compound(s) in the composition may vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • the polyhydroxylated bile acid such as tetrahydroxylated bile acid
  • the polyhydroxylated bile acid can be provided in combination with FXR agonist in a single formulation.
  • the polyhydroxylated bile acid such as tetrahydroxylated bile acid
  • Toxicity of the combination therapy can be determined using standard techniques, for example, by testing in cell cultures or experimental animals or subjects and determining the therapeutic index, i.e., the ratio between the LD50 (the dose lethal to 50% of the population) and the ED50 (the minimum effective dose for 50% of the population) for non-human animals or the ratio between the TD50 (the dose toxic to 50% of the population) and the ED50 (the minimum effective dose for 50% of the population) for humans.
  • the therapeutic index i.e., the ratio between the LD50 (the dose lethal to 50% of the population) and the ED50 (the minimum effective dose for 50% of the population) for non-human animals or the ratio between the TD50 (the dose toxic to 50% of the population) and the ED50 (the minimum effective dose for 50% of the population) for humans.
  • Other methods that may be used to determine toxicity of the compounds of the invention include, but are not limited to, histological abnormality by H&E staining, trichrome staining or the like; changes in bile flow rate, and/or clearance of other bile substances (for example, as determined by bile duct cannulation); HPLC analysis, enzymatic assays or the like; changes in liver indicator profiles, for example level of bilirubins, level of ALP (alkaline phosphatase), level of ALT (alanine aminotransferase), level of AST (aspartate aminotransferase), level of g-GT (Gamma-Glutamyl Transpeptidase), or the like.
  • histological abnormality by H&E staining, trichrome staining or the like changes in bile flow rate, and/or clearance of other bile substances (for example, as determined by bile duct cannulation); HPLC analysis, enzymatic as
  • the maximum tolerated dose is the highest regularly administered dose of a compound or composition that does not cause overt toxicity (e.g. does not cause unacceptable side effects) in a subject study over a period of time.
  • the subject may be a human, or an animal, such as a mouse or a rat, for example.
  • the regularly administered dose may be a daily dose, administered as a single bolus; alternately the daily dose may be divided into two or more partial doses so that the subject receives the total daily dose over time.
  • the period of time of the study may vary from a few days to a few months, for example about 10, 20, 30, 60, 90 or 120 days, or any value therebetween.
  • overt toxicity may include, but are not limited to, appreciable death of cells or organ dysfunction, toxic manifestations that are predicted materially to reduce the life span of the subject, or 10% or greater retardation of body weight gain.
  • the claimed combination may be provided together with other compounds (for example, nucleic acid molecules, small molecules, peptides, or peptide analogues), in the presence of a liposome, an adjuvant, or any pharmaceutically or physiologically acceptable carrier, in a form suitable for administration to humans or animals.
  • treatment with the claimed combination according to the invention may be combined with more traditional and existing therapies for biliary disorders or disorders resulting in or potentially resulting in hepatotoxicity, or with existing nutritional supplements for stimulating bile flow, or for GI disorders.
  • the claimed combination according to the invention is administered where the approved therapeutic agent for cholestasis, ursodeoxycholate, is ineffective.
  • the claimed combination according to the invention is administered together with ursodeoxycholate or a variant or derivative thereof (e.g., sulfated ursodeoxycholate,
  • Conventional pharmaceutical or nutritional supplement formulation practice may be employed to provide suitable formulations or compositions to administer the claimed
  • any appropriate route of administration may be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracistemal, intraperitoneal, intranasal, aerosol, or oral administration.
  • Therapeutic formulations may be in the form of liquid solutions or suspensions; for oral administration, formulations may be in the form of tablets or capsules; and for intranasal formulations, in the form of powders, nasal drops, or aerosols.
  • Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes.
  • Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds.
  • Other potentially useful parenteral delivery systems for modulatory compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
  • the claimed combination may be administered to a subject in an amount sufficient to stop or slow cholestasis or to maintain or increase bile flow or to ameliorate portal hypertension.
  • the claimed combination may be administered to a subject in an amount sufficient to stimulate bile flow.
  • the claimed combination can also provide therapeutic benefit to patients suffering from inherited cholestatic liver disease, from drug-induced cholestasis arising from the Bile Salt Export Pump (BSEP)-inhibitory activity of certain drugs, or from other biliary disorders, and can help alleviate acute hepatotoxic reactions brought about by drugs and inflammatory conditions which impact biliary function.
  • the claimed combination can be used in combination with a compound that does not inhibit BSEP.
  • the claimed combination can be used in combination with a compound that does not exhibit a preferential affinity for BSEP over P-glycoprotein (Mdr1).
  • the claimed combination can be used under conditions where BSEP is functional, for example, in combination with ursodeoxycholate.
  • the claimed composition can enhance the therapeutic effect of an FXR agonist. Accordingly, in some embodiments, the present disclosure provides a method for enhancing the therapeutic effect of a farnesoid X receptor agonist by administering a
  • kits A kit including the claimed composition, along with instructions for use of the compound or composition, is provided.
  • the kit may be useful for treating a biliary disorder or GI disorder in a subject, and the instructions may include, for example, dose concentrations, dose intervals, preferred administration methods or the like.
  • EXAMPLE 1 [00101] In a first study, a 1% THBA (3 a, 6 a, 7 a, 12 a-tetrahydroxy-5 b-cholan-24-oic acid) and 0.03% OCA were fed to a mouse model of human PSC and PFIC (female mice, starting at 3 weeks of age) for 17 weeks in a form of dietary supplementation (w/w), either individually or in combination. The body weight and food consumption were recorded weekly during treatment. After the treatment, mice were euthanized and tissues/organs were sampled for further analysis.
  • EXAMPLE 2 [00104] In another study, a 1% THBA (3 a, 6 a, 7 a, 12 a-tetrahydroxy-5 b-cholan-24-oic acid) and tropifexor (TXR) were fed to female Mdr2 -/- mice, of around 12 weeks of age, for 26- 28 days in a form of dietary supplementation (w/w), either individually or in combination. The body weight and food consumption were recorded weekly during treatment. After the treatment, mice were euthanized and tissues/organs were sampled for further analysis. Dietary

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Abstract

La présente invention concerne, en partie, une polythérapie d'un acide biliaire polyhydroxylé et d'un agoniste du récepteur famésoïde X. La présente invention concerne également, en partie, une composition pharmaceutique comprenant un agoniste du récepteur farnésoïde X et un acide biliaire polyhydroxylé dans la préparation d'un médicament pour traiter un trouble biliaire ou un trouble gastro-intestinal
PCT/IB2020/055097 2019-05-29 2020-05-29 Combinaison d'un acide biliaire polyhydroxylé et d'un agoniste du récepteur farnésoïde x WO2020240483A1 (fr)

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CN202080039658.7A CN113950329A (zh) 2019-05-29 2020-05-29 多羟基化胆汁酸和法尼醇x受体激动剂的联合
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Citations (2)

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